Abstract

There is conflicting evidence about comorbid personality pathology in
depression treatments.

Aims

To test the effects of antidepressant drugs and cognitive therapy in people
with depression distinguished by the presence or absence of personality
disorder.

Method

Random assignment of 180 out-patients with depression to 16 weeks of
antidepressant medication or cognitive therapy. Random assignment of
medication responders to continued medication or placebo, and comparison with
cognitive therapy responders over a 12-month period.

Results

Personality disorder status led to differential response at 16 weeks; 66%
v. 44% (antidepressants v. cognitive therapy respectively)
for people with personality disorder, and 49% v. 70% (antidepressants
v. cognitive therapy respectively) for people without personality
disorder. For people with personality disorder, sustained response rates over
the 12-month follow-up were nearly identical (38%) in the prior cognitive
therapy and continuation-medication treatment arms. People with personality
disorder withdrawn from medication evidenced the lowest sustained response
rate (6%). Despite the poor response of people with personality disorder to
cognitive therapy, nearly all those who did respond sustained their
response.

Conclusions

Comorbid personality disorder was associated with differential initial
response rates and sustained response rates for two well-validated treatments
for depression.

Although current American Psychiatric Association treatment guidelines
state that `cognitive behavioral therapy may be more effective than other
treatments for depressed individuals with personality
disorders',1 this
statement appears to be largely based on a misunderstanding of data from the
Treatment of Depression Collaborative Research
Program.2,3
The results from this project did not reveal a personality disorder ×
treatment interaction, but rather a non-significant trend whereby people with
no comorbid personality disorder responded more poorly to cognitive therapy
than did people with personality disorder. Subsequent studies have not
supported the claim that the presence of personality disorder predicts
favourable response to cognitive
therapy.4 Moreover,
the conclusions from two recent meta-analyses reflect the controversy
regarding whether comorbid personality pathology affects response to treatment
for
depression.5,6
One reported that people with depression and comorbid personality disorder
experienced poorer response when receiving either cognitive therapy or
pharmacotherapy.6
The other, which included only trials of antidepressant medication, reported
no difference in response as a function of personality
pathology.5

We present data drawn from a multi-site randomised controlled trial
comparing cognitive therapy and paroxetine for individuals diagnosed with
moderate-to-severe
depression.7,8
We focus on whether the presence of comorbid personality disorder predicts
differential response to cognitive therapy and pharmacotherapy, and we explore
the effect of comorbid personality disorder on relapse once treatment is
terminated.

Method

The sample characteristics, treatment protocols and main treatment outcome
findings have been reported
elsewhere.7,8
Briefly, the sample consisted of 240 out-patients with depression (measured
using the Structured Clinical Interview for DSM–IV
Diagnosis)9 who
registered a score of 20 or higher on the modified 17-item version of the
Hamilton Rating Scale for Depression
(HRSD).10
Personality pathology was assessed at intake using the Structured Clinical
Interview for DSM–III–R Personality
Disorders.11 Among
the entire sample, 48% of individuals met criteria for at least one comorbid
personality disorder. As was done in the Treatment of Depression Collaborative
Research Program, participants with antisocial (n=3) and schizotypal
(n=1) personality disorders were excluded from the
trial.2 Those
meeting criteria for borderline personality disorder (n=8) were also
excluded. The treatments under investigation were judged to be either
ill-suited or too brief for individuals with depression comorbid with any of
these three disorders. The distributions of personality disorders (shown in
the online table DS1) were similar between the treatment arms and resemble
those found in other samples of out-patients with
depression.12 The
institutional review boards of the University of Pennsylvania and Vanderbilt
University approved the study's protocols. All participants provided written
informed consent.

Treatment

Participants were randomly assigned to receive cognitive therapy
(n=60), antidepressant treatment with paroxetine (n=120) or
pill placebo (n=60) (Fig.
1). After 8 weeks of the 16-week acute treatment phase, the
placebo arm was terminated and individuals who had been receiving placebo were
offered antidepressant treatment at no cost. Because 8 weeks of treatment is
generally not regarded as sufficient to treat people with comorbid personality
disorders, comparisons that include the placebo group were not included in the
analyses below.

The criterion for response at 16 weeks was an HRSD score of 12 or lower. In
order to limit the effect of transient mood fluctuations on the response
designation, additional constraints required participants to have scored 14 or
less at week 14, or 12 or less at weeks 10 and 12. Individuals who scored
higher than 12 at week 16 were still considered `responders' if they had
scored 12 or below at weeks 12 and 14, and again scored 12 or below at an
additional evaluation at 18 weeks. Response at 16 weeks also required the
completion of acute treatment.

Of the 180 people assigned to antidepressants or cognitive therapy, 104
people met the response criteria at 16 weeks and were entered into the
12-month continuation phase of the study. Half of the responders from the
antidepressant group (n=35) were randomly assigned to be withdrawn
from medication onto pill placebo (continuation placebo) while the other half
(n=34) were continued on medication (continuation medication)
throughout the 1-year continuation phase. In the cognitive therapy condition,
regular therapeutic contact ceased at the end of the acute phase of treatment.
Treatment responders (n=35) could use up to three 1-hour booster
sessions throughout the 1-year continuation phase. When individuals on
antidepressants were randomised to continuation placebo or continuation
medication at the beginning of the continuation phase, the process was triple
blind – participants, pharmacotherapists and evaluators did not know
which individuals were receiving active medication.

Outcome measures

The primary outcome measure was the 17-item version of the HRSD. During the
acute phase, assessments with evaluators masked to treatment condition were
held weekly for the first 4 weeks and biweekly from week 6 to week 16. During
the continuation phase, assessments were conducted during each of the first 2
weeks, biweekly through to the end of the second month, and monthly
thereafter. Relapse was defined as a score of 14 or greater on the HRSD during
two consecutive weeks (ad hoc assessments were scheduled as needed to
confirm this temporal component). If a person experienced a worsening of
symptoms in the interval between assessments, the timing of relapse was
ascertained using the Longitudinal Interval Follow-up
Evaluation,13
conducted at the next assessment. Of the 45 participants who were judged to
have relapsed, 11 were ascertained using this instrument.

Statistical analyses

The primary statistical analyses examined whether there were differences in
efficacy between the two treatments as a function of personality disorder
status, by examining:

the percentage of individuals meeting response criteria;

change in average depression severity scores;

the percentage who met response criteria and did not relapse post-treatment
(sustained response).

Data from all participants randomised to treatment were included in all
three sets of (intent-to-treat) analyses. In the case of attrition, all data
collected up to the date of attrition were included. In each analysis, the
treatment × personality disorder status interaction term was of primary
interest.

For the acute phase data, Cochran–Mantel–Haenszel tests were
used to assess differential response/non-response as a function of treatment
and personality disorder status, stratified across the two
sites.14 Odds
ratios (ORs), confidence interval (CI) bands and interaction effects were
assessed using a logistic regression model based on the likelihood ratio χ
2
statistic.15
Continuous data were examined with multiple regression techniques using a last
observation carried forward approach and with hierarchical linear modeling.
The hierarchical linear modeling approach adjusts for repeated measures with
nested random
effects.16,17
Using this approach, each person's growth curve and true HRSD score at the end
of treatment can be estimated from a collection of individual-specific
parameters.18 For
all hierarchical linear modeling analyses reported, an unstructured covariance
structure was assumed in order to model random intercepts and slopes. Two
baseline scores were obtained for all participants, allowing for a full
intent-to-treat analysis while at the same time covarying for each person's
initial baseline depression severity score. All models were performed using
SAS Version 9.0 for Windows, PROC MIXED for hierarchical linear modelling
analyses, PROC GLM for multiple regression analyses, PROC FREQ for
Cochran–Mantel–Haenszel tests, and PROC GENMOD for Logistic
Regression (SAS Institute Inc, Cary, North Carolina, USA).

The Cox proportional hazards model was used to estimate attrition rates and
relapse rates.19
Because a differential response rate for people with and without personality
disorder emerged between the two treatments (see below), the Cox proportional
hazards technique is inappropriate on its own to estimate survival rates
during the continuation phase. Any indication of differential relapse might be
an artifact of a differential sieve through which individuals who would be at
greatest relapse risk already had failed to respond to a particular
treatment,20 and
therefore did not enter the continuation phase. To address this concern,
estimated survival curves from Cox proportional hazards regression models were
weighted by the proportion of people who responded in each treatment arm. This
procedure estimates the percentage of people who both responded to treatment
and maintained that response throughout the 1-year continuation phase. In the
original publication, four possibly confounding covariates (dysthymia,
atypical depression, number of prior episodes and gender) were entered in the
survival analyses;8
these were performed using the present models as well. These models were
performed using the SAS procedure, PROC PHREG.

Results

Attrition

The overall rate of participant attrition was detailed in the original
publication.7
Although survival analyses revealed no overall difference between people with
and without personality disorder (χ21=0.32,
P=0.57), a statistically non-significant trend-level personality
disorder status × treatment interaction did emerge
(χ21=2.72, P<0.10). This effect was
driven in large part by the fact that the attrition rate was lower for people
with personality disorder (12%) than for people without personality disorder
(21%) in the antidepressant arm, and lower for people without personality
disorder (12%) than for people with personality disorder (22%) in the
cognitive therapy arm.

Outcome of acute treatment

Categorical response analyses

There was a significant interaction between treatment and personality
disorder status in acute treatment response
(χ21=6.77, P=0.009). As displayed by the
narrow bars in Fig. 2, people
with personality disorder showed a non-significant trend in favour of
antidepressants; 66% (95% CI 54–78) met response criteria compared with
44% (95% CI 25–63) in the cognitive therapy arm
(Cochran–Mantel–Haenszel χ21=3.42,
P=0.06; OR=2.42, 95% CI 0.96–6.28). The reverse pattern was
observed, as a non-significant trend, for people without personality disorder,
with 70% (95% CI 54–86) meeting response criteria in the cognitive
therapy arm, compared with 49% (95% CI 36–62) in the antidepressant arm
(Cochran–Mantel–Haenszel χ21=3.20,
P=0.07; OR=2.28, 95% CI 0.94–5.81). The tests of the main
effects of treatment, personality disorder status and the three-way site ×
treatment × personality disorder status interaction were
non-significant (all χ2s<0.43, all Ps>0.51).

The percentage of individuals in each treatment arm meeting response and
sustained response criteria. ADM, antidepressant medication; CT, cognitive
therapy. The narrow bars display the proportion of people who met response
criteria in the two treatments (antidepressants and cognitive therapy) at the
end of the 16-week acute phase. The wide bars represent the estimated
proportion of individuals who survived the 12-month follow-up period without a
relapse. Bars on the left half of the figure represent individuals diagnosed
with a comorbid personality disorder; bars on the right represent individuals
who did not have a comorbid Axis-II diagnosis.

Continuous response analyses

In the original publication of the treatment outcome data, the authors
reported a significant site × treatment interaction in the hierarchical
linear modelling
analyses;7 this
interaction term was added to the models described below. Controlling for
initial depression severity, the test of the treatment × personality
disorder status interaction on estimates of week 16 HRSD scores was
significant in the last observation carried forward (F1,173=4.18,
P=0.04) and hierarchical linear modeling analyses
(F1,173=4.32, P=0.04; Cohen's d=0.76 (95% CI
0.32–1.20)). Follow-up hierarchical linear modelling analyses among
people with and without personality disorder yielded a non-significant trend
in favour of antidepressants for people with personality disorder
(t173=–1.69, P=0.09) and a non-significant
treatment effect in people without personality disorder
(t173=1.24, P=0.22). The test of the treatment ×
personality disorder status interaction on the linear slope estimates
of symptom change, though in the same direction as those obtained in the last
observation carried forward and hierarchical linear modelling intercept
analyses, was not significant (F1,171=1.98,
P=0.16; Cohen's d=0.40 (95% CI –0.04 to 0.84)).

Potential confounds

To address the possibility that people with personality disorder differed
from those without personality pathology in other important ways, we examined
eight history of illness variables, two depression subtype variables, four
composite Axis I comorbidity variables, seven demographic variables and, for
people in the antidepressant arm, dosage and augmentation, to determine
whether people with and without personality disorder differed at the
P<0.10 level. As shown in online table DS2, nine of these
variables differed between the two groups. All nine variables were entered
simultaneously into each of the models reported above. For the model
predicting categorical response, as well as the hierarchical linear model
predicting end of treatment HRSD scores, the personality disorder status ×
treatment interaction remained significant even with the simultaneous
addition of all nine variables (χ21=5.59,
P=0.02 for the categorical analysis; F1,164=4.13,
P=0.04 for the hierarchical linear model). In the last observation
carried forward analysis, the personality disorder status × treatment
interaction became a non-significant trend (F1,164=3.54,
P=0.06).

Individual personality disorder diagnoses

The results reported thus far were achieved by comparing all participants
with at least one personality disorder diagnosis with participants with no
personality disorder diagnosis. In order to better determine what was driving
the observed effects, we conducted exploratory analyses examining the
relations for individual personality disorders. The strongest pattern occurred
for people diagnosed with personality disorder not otherwise specified (NOS),
wherein 12 of 16 people (75%) responded to antidepressants and 3 of 9 (33%)
responded to cognitive therapy (OR=6.09, 95% CI 1.09–42.87, in favour of
antidepressants over cognitive therapy). In order to examine this effect
further, we assigned individuals diagnosed with personality disorder NOS to
the personality disorder cluster in which their highest concentration of
symptoms was observed. For example, a broad-band Cluster C category was formed
by combining individuals with personality disorder NOS for whom the highest
concentration of symptoms fell in Cluster C with those individuals who
actually received a Cluster C diagnosis. The effect of personality disorder
status was the strongest for individuals in the broad-band Cluster B category.
Of the 16 people in the broad-band Cluster B grouping, 6 of the 9 individuals
treated with antidepressants responded, whereas only 1 of 7 individuals being
treated with cognitive therapy responded (OR=15.03, 95% CI 1.36–515.92).
For people in the broad-band Cluster C group, 32 of 47 (68%) responded to
antidepressants, whereas 10 of 19 (53%) responded to cognitive therapy
(OR=1.97, 95% CI 0.65–5.98). For those in the broad-band Cluster A
group, 2 of 4 responded to cognitive therapy v. 1 of 4 who responded
to antidepressants (OR=3.28, 95% CI 0.16–137.50).

Sustained response through the 12-month continuation phase

For the 12-month continuation phase, the survival rates of the three
treatment arms (prior cognitive therapy, continuation placebo and continuation
medication) were estimated for individuals with and without personality
disorder. Sustained response estimates for each group were then calculated by
computing the product of these survival estimates and the group's treatment
response rate (e.g. for people with personality disorder who had received
antidepressant treatment, survival estimates for both the continuation
medication and continuation placebo arms were multiplied by the percentage of
people with personality disorder who responded to acute antidepressant
treatment). Analysis of these estimates revealed a significant treatment ×
personality disorder status interaction in the percentage of people
who showed a sustained response through the end of the 12 months
(χ22=6.13, P=0.047). For people with
personality disorder, a significant main effect of treatment emerged
(χ22=11.94, P=0.003). The wide bars in
Fig. 2 show that despite the
fact that a higher percentage of people with personality disorder responded to
treatment (and hence entered the continuation phase) in the antidepressant arm
(66%) compared with the cognitive therapy arm (44%), an estimated 38% of
patients (95% CI 20–56) initially randomised to cognitive therapy
evidenced sustained response. With a higher relapse rate in the continuation
medication arm, a nearly identical estimate of the proportion of people with
sustained response was obtained in this group (38% (95% CI 21–55)).
People with personality disorder who had previously received antidepressants
but were withdrawn onto continuation placebo tended to relapse at an extremely
high rate. Only 6% of these people (95% CI –3 to 15) exhibited sustained
response. Specific contrasts revealed that, for people with personality
disorder, prior cognitive therapy and continuation medication were each
superior to continuation placebo on the sustained response variable
(χ21=9.80, P=0.002 for continuation
medication v. continuation placebo; χ
21=9.15, P=0.003 for prior cognitive
therapy v. continuation placebo). There was no difference in
estimated sustained response rates between prior cognitive therapy and
continuation medication for this group (χ21=0.002,
P=0.97).

For people without personality disorder, the main effect of treatment was
not significant in the analysis of sustained response
(χ21=4.54, P=0.103).
Figure 2 shows that for people
initially randomised to receive cognitive therapy, 43% (95% CI 26–60)
exhibited sustained response compared with 23% (95% CI 8–38) for those
initially randomised to receive antidepressant treatment who were then
assigned to continuation placebo, and 21% (95% CI 7–35) for those who
were assigned to antidepressant treatment and then were assigned to
continuation medication.

Discussion

The primary purpose of this investigation was to determine whether
personality pathology predicts differential response to two generally
effective treatments for depression. In this sample of people with
moderate-to-severe depression, short-term cognitive monotherapy proved
relatively ill-suited for those with comorbid personality disorder, a pattern
consistent with findings from the Nottingham Study of Neurotic Disorder in
which cognitive therapy and self-help treatment were less effective for people
with comorbid personality disorder than for those without Axis II
pathology.21
Indeed, in the present study, fewer than half of the people with personality
disorder responded to cognitive therapy. Those who did respond, however,
tended to sustain their response throughout the ensuing 12-month continuation
phase.

Antidepressants, on the other hand, worked particularly well to reduce
depressive symptoms for patients diagnosed with comorbid personality
pathology. Although individuals with and without personality disorder differed
in several respects, including the incidence of comorbid anxiety disorders,
none of these factors accounted statistically for the differential treatment
effects. Results from the continuation phase of the study further support the
conclusion that antidepressants had potent effects in this group in that
nearly all of the people with personality disorder who were withdrawn from
medication relapsed. For people with depression who did not have diagnosed
personality pathology, there was a suggestion in the data that cognitive
therapy was particularly effective at reducing depressive symptoms, relative
to antidepressants.

Limitations

The pattern of findings in regard to acute treatment response was
consistent across the three different analytical methods, and the test of
significance for the interaction of interest was met in all three. However, in
the analysis that employed hierarchical linear modelling, the interaction of
interest was significant only in the prediction of 16-week scores and not in
the prediction of symptom change over time. This inconsistency may have arisen
because of the fact that hierarchical linear modelling analyses can lead to
misleading estimates of improvement rates in data-sets containing non-random
attrition.22,23
Consistent with the observation that people with personality disorder assigned
to cognitive therapy and people without personality disorder assigned to
antidepressants fared more poorly than the other two groups, individuals
within these groups also tended to have higher rates of attrition. This is
another indication that antidepressants were better-suited to people with
personality disorder in this trial and that cognitive therapy was better
suited to people without personality disorder. In addition, between-treatment
differences in outcome within the subgroups of individuals with and without
personality disorder were at the level of non-significant trends. Since these
tests were associated with relatively low power, these comparisons will be
most useful to the field as constituents of future meta-analyses that will
combine the current findings with attempts to replicate these results.

A second limitation involves the duration of the active treatments. The
differences between cognitive therapy and antidepressants in relation to
personality disorder status may have depended, in part, on the fact that the
treatments were brief, relative to the durations recommended for treating
people with depression who have comorbid personality disorder. Given more
time, cognitive therapy might have been as effective as antidepressants for
people with personality disorders, and antidepressants might have been as
effective as cognitive therapy for people without personality disorders.
Nevertheless, short-term treatment did lead to response percentages of up to
two-thirds of people with personality disorder in the antidepressant arm, as
well as for people without personality disorder in cognitive therapy.

Third, prospective participants with diagnosed schizotypal, antisocial or
borderline personality disorders were excluded from the trial. Thus, these
results do not, strictly speaking, generalise to the population that includes
people with these comorbidities. However, only 5% of otherwise eligible
participants were excluded because they received one of these diagnoses, and
all but one of these individuals was excluded because of a Cluster B
diagnosis. People in this trial whose highest concentration of personality
disorder symptoms occurred in Cluster B showed a particularly strong response
to antidepressants relative to cognitive therapy. This suggests that the
pattern we observed might be even stronger in a sample that includes all Axis
II comorbidities.

Future directions

Because the primary medication used in this study, paroxetine, has
demonstrated efficacy in treating depression with comorbid anxiety disorders,
it might have been expected that the antidepressants' relative efficacy for
people with personality disorder was due to its superiority for patients with
Cluster C personality
disorders.24
However, the numerical advantage for antidepressants was strongest for people
with Cluster B personality pathology. One possible explanation for this result
is suggested by research demonstrating that people with Cluster B personality
disorders display deficits in cortical regions thought to underlie the
regulation of emotion and the inhibition of impulsive
aggression,25 and
from studies that demonstrate that selective serotonin reuptake inhibitors can
reduce mood lability, anger and impulsive behaviour in humans and
animals.26–28
Future studies might attempt to further investigate these mechanisms in people
with depression and this type of personality pathology. In addition, the
surprisingly high rate of relapse among people with personality disorder
withdrawn from medication should be examined in future research, as the
mechanism driving this effect is currently unclear.

Clinical implications

The pattern of results from this study suggests possible prescriptive
recommendations regarding short-term treatment for people with
moderate-to-severe depression as a function of comorbid personality pathology.
Evidence from this study, consistent with findings from other investigations,
suggests that for people with depression with a comorbid personality disorder,
paroxetine treatment is more likely than cognitive therapy to alleviate their
depressive symptoms in the short term. Because of a higher relapse rate for
people receiving continuation medication, short-term cognitive therapy may
produce rates of sustained response roughly equivalent to those achieved with
sustained antidepressants, provided that booster sessions are given to
individuals receiving cognitive therapy. Given the relatively low relapse rate
among people with personality disorder who responded to cognitive therapy, the
combination of antidepressants and cognitive therapy might be especially
valuable for these people. Individuals without a personality disorder
diagnosis fared better during acute treatment and exhibited a higher sustained
response rate while receiving cognitive therapy, compared with
antidepressants. Indeed, these people appeared to be equally susceptible to
relapse following acute treatment with antidepressants regardless of whether
they were continued on medication or withdrawn onto placebo. This pattern, if
replicated, could lead to the consideration of cognitive therapy as a
first-line treatment for people with depression who do not have a personality
disorder.

Acknowledgments

We thank our colleagues for contributing to this research. J.C.F. drafted
the manuscript and conducted the statistical analyses. R.J.D. and S.D.H. were
the principal investigators and oversaw the implementation of cognitive
therapy at the respective sites. J.D.A. and R.C.S. were the co-principal
investigators and supervised the implementation of medication treatment. R.G.
provided methodological and statistical expertise. All authors had full access
to all of the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis. We also thank our colleagues
who helped make this research possible. Paula R. Young and Margaret L. Lovett
served as the study coordinators. John P. O'Reardon, Ronald M. Salomon and the
late Martin Szuba served as study pharmacotherapists (along with J.D.A and
R.C.S.). Cory P. Newman, Karl N. Jannasch, Frances Shusman and Sandra Seidel
served as the cognitive therapists (along with R.J.D. and S.D.H.). Jan Fawcett
provided consultation with regard to the implementation of clinical management
pharmacotherapy. Aaron T. Beck, Judith Beck, Christine Johnson and Leslie
Sokol provided consultation with respect to the implementation of cognitive
therapy. Madeline M. Gladis and Kirsten L. Haman oversaw the training of the
clinical interviewers, and David Appelbaum, Laurel L. Brown, Richard C.
Carson, Barrie Franklin, Nana A. Landenberger, Jessica Londa-Jacobs, Julie L.
Pickholtz, Pamela Fawcett-Pressman, Sabine Schmid, Ellen D. Stoddard, Michael
Suminski and Dorothy Tucker served as project interviewers. Joyce L. Bell,
Brent B. Freeman, Cara C. Grugan, Nathaniel R. Herr, Mary B. Hooper, Miriam
Hundert, Veni Linos and Tynya Patton provided research support. This research
was supported by grants MH50129 (R10), MH55875 (R10), MH01697 (K02) and
MH01741 (K24) from the National Institute of Mental Health, Bethesda,
Maryland, USA. GlaxoSmithKline provided medications and pill placebos for the
trial.